# NM_004035.7(ACOX1):c.25C>A (p.Arg9=)

https://sugi.bio/variant/acox1-p-arg9

## Summary

**ACOX1 p.Arg9= (c.25C>A)** is classified **Likely benign** in ACOX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-09). No allele count reported in gnomAD v4.1 (AN 1,612,130); Associated with peroxisomal acyl-CoA oxidase deficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs765997588 · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,612,130)

## For patients & families {#patients}

This is a change in the ACOX1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to peroxisomal acyl-CoA oxidase deficiency.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ACOX1 is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Peroxisomal acyl-CoA oxidase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sensorineural hearing impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Abnormality of visual evoked potentials — Very frequent (99-80%)
- Hypodontia — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004543/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACOX1](https://sugi.bio/atlas/gene/ACOX1/) |
| Protein change (HGVS p.) | p.Arg9= |
| Coding change (HGVS c.) | c.25C>A |
| MANE Select transcript | [NM_004035](https://www.ncbi.nlm.nih.gov/nuccore/NM_004035) |
| dbSNP | [rs765997588](https://www.ncbi.nlm.nih.gov/snp/rs765997588/) |
| Variant type | single nucleotide variant |
| Location | chr17:75979049-75979049 (GRCh38) |
| ClinVar | [VCV2759315](https://www.ncbi.nlm.nih.gov/clinvar/variation/2759315/) |

**All HGVS expressions:** `NC_000017.10:g.73975130G>T`, `NC_000017.11:g.75979049G>T`, `NG_008190.1:g.5315C>A`, `NG_137591.2:g.810G>T`, `NM_001185039.2:c.-264C>A`, `NM_004035.7:c.25C>A`, `NM_007292.6:c.25C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.287, GERP 1.57, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.41**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,612,130)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ACOX1** population constraint: LOEUF 0.67, pLI 1.7103e-05, missense-Z 3.067; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Mitchell syndrome** — Definitive (AD)
- **peroxisomal acyl-CoA oxidase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.95, 87% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ACOX1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ACOX1's established molecular role includes acyl-CoA oxidase activity.


### Pathways affected {#pathways}

ACOX1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Beta-oxidation of very long chain fatty acids](https://reactome.org/content/detail/R-HSA-390247) | other |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | other |
| [Peroxisomal protein import](https://reactome.org/content/detail/R-HSA-9033241) | electronic |
| [TYSND1 cleaves peroxisomal proteins](https://reactome.org/content/detail/R-HSA-9033500) | electronic |
| [alpha-linolenic acid (ALA) metabolism](https://reactome.org/content/detail/R-HSA-2046106) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** acyl-CoA oxidase activity, PDZ domain binding, protein homodimerization activity, FAD binding, long-chain fatty acyl-CoA oxidase activity.

**Biological process:** very long-chain fatty acid metabolic process, generation of precursor metabolites and energy, lipid metabolic process, prostaglandin metabolic process, fatty acid catabolic process, peroxisome fission.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-09.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-09 |

## Associated conditions {#conditions}

[peroxisomal acyl-CoA oxidase deficiency](https://sugi.bio/atlas/disease/peroxisomal-acyl-coa-oxidase-deficiency/).

**Reported phenotype names (ClinVar):** Acyl-CoA oxidase deficiency, Peroxisomal acyl-CoA oxidase deficiency, STRAIGHT-CHAIN ACYL-CoA OXIDASE DEFICIENCY, Pseudoneonatal adrenoleukodystrophy.

## Similar variants {#similar}

Related ACOX1 variant pages (same residue, condition, or type): [ACOX1 p.Arg9Gly](/variant/acox1-p-arg9gly), [ACOX1 c.538+1G>A](/variant/acox1-c-538-plus-1g-a), [ACOX1 c.945-1G>C](/variant/acox1-c-945-minus-1g-c), [ACOX1 p.Arg148Ter](/variant/acox1-p-arg148ter), [ACOX1 p.Arg302Ter](/variant/acox1-p-arg302ter), [ACOX1 p.Arg94Ter](/variant/acox1-p-arg94ter), [ACOX1 p.Asn237Ser](/variant/acox1-p-asn237ser), [ACOX1 p.Gln114Ter](/variant/acox1-p-gln114ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2759315). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*